Project Summary Essential hypertension is a polygenetic disease afflicting nearly 1 billion individuals worldwide. It predisposes to cardiac hypertrophy, stroke and chronic renal failure. Of the individuals offered antihypertensive drugs, only one third achieve blood pressure control due to the high cost, side effects and noncompliance associated with the daily, multi-drug therapy that is often required. In this regard, the long-term expression of vasodilator proteins would be extremely advantageous to avoid the high cost and inconvenience associated with daily drug administration, and also to minimize the blood pressure fluctuations caused by short-acting antihypertensive drugs. Of major interest as a candidate vasodilator protein is the high-conductance, calcium- activated K+ (BK) channel that is expressed in the surface membrane of vascular smooth muscle cells (VSMCs) and other cell types. The BK channel is activated by rises in intravascular pressure, and acts as a compensatory mechanism to mediate vasodilation. Thus, we envision that using adeno-associated viral (AAV) delivery to overexpress the BK channel in arterial VSMCs, we can establish a channel reserve of compensatory dilator proteins that will provide long-term antihypertensive therapy. Based on this premise, this proposal explores the hypothesis that: Smooth muscle-specific delivery of the BK channel gene by adeno- associated-virus (AAV) represents a therapy for the long-term control of high blood pressure. In exciting proof- of-principle studies, we observed that AAV-mediated delivery of the BK channel gene can be preferentially targeted to the vasculature using a smooth muscle-specific promoter, and this therapy lowers blood pressure in hypertensive mice. Based on these findings, we have designed four specific aims that will: Optimize BK channel gene delivery (Aim 1), assess the antihypertensive effect of AAV delivery of BK channels in two mouse models of hypertension (Aim 2), evaluate if the transduced BK channels enhance K+ current and retain normal properties in VSMC membranes (Aim 3), and evaluate the vasodilator benefit of AAV-mediated delivery of BK channels in vitro and in vivo (Aim 4). Clearly, in order to reduce the incidence of hypertension in the general population, vascular-specific, long-term antihypertensive treatments must be introduced into clinical care. In this respect, the findings of our project suggest that using AAV-mediated delivery to target BK channels to arterial VSMCs normalizes hypertension in the established phase of the disease, suggesting a new paradigm for antihypertensive treatment that avoids the daily administration of antihypertensive drugs.